Efficacy of platelet-inspired hemostatic nanoparticles on bleeding in Von Willebrand disease murine models

Abstract

The lack of innovation in Von Willebrand disease (VWD) originates from many factors including the complexity and heterogeneity of the disease but also from a lack of recognition of the impact of the bleeding symptoms experienced by VWD patients. Recently, a few research initiatives aiming to move past replacement therapies using plasma-derived or recombinant Von Willebrand factor (VWF) concentrates have started to emerge. Here we report an original approach using synthetic platelet (SP) nanoparticles for treatment of VWD type 2B (VWD-2B) and severe VWD (type 3 VWD). SP are liposomal nanoparticles decorated with peptides enabling them to concomitantly bind to collagen, VWF and activated platelets. In vitro, using various microfluidic assays, we show the efficacy of SP to improve thrombus formation in VWF-deficient condition (with human platelets) or using blood from VWD-2B mice and VWF-deficient mice (VWF-KO, i.e., type 3 VWD). In vivo, using a tail clip assay, SP treatment reduced blood loss by 35% in VWD-2B mice and 68% in VWF-KO mice. Additional studies using nanoparticles decorated with various combinations of peptides demonstrated that the collagen binding peptide, although not sufficient by itself, was absolutely crucial for SP efficacy in VWD-2B while all three peptides appeared necessary for VWF-KO mice. Clot imaging by immunofluorescence and scanning electron microscopy revealed that SP treatment of VWF-KO mice led to a strong clot, similar to those obtained in wild-type mice. Altogether, our results show that SP could represent an attractive therapeutic alternative for VWD, especially considering their long half-life and stability.

Magnetic Metal–Organic Framework-Based Nanoplatform with Platelet Membrane Coating as a Synergistic Programmed Cell Death Protein 1 Inhibitor against Hepatocellular Carcinoma

“…Furthermore, after separating tumor tissue from the liver, the tumor tissues from the PmMN@DiD group and the PmMN@DiD & magnetic field group exhibited stronger fluorescent signals compared to free DiD and MN@DiD (Figure C, E), which suggested that the Pm coating facilitated effective targeting and prolonged retention of nanoplatforms within HCC. It is well-known that HCC tissue contains an abundance of collagen, , and collagen can serve as an agent for platelet aggregation. , We hypothesized that the PmMN@Om&As might target and adhere to HCC tissue through the recognition of Pm coating to collagen. We substantiated this hypothesis through a simulated blood perfusion experiment.…”

“…It is well-known that HCC tissue contains an abundance of collagen, 63,64 and collagen can serve as an agent for platelet aggregation. 65,66 We hypothesized that the PmMN@Om&As might target and adhere to HCC tissue through the recognition of Pm coating to collagen. We substantiated this hypothesis through a simulated blood perfusion experiment.…”

Progress in von Willebrand Disease Treatment: Evolution towards Newer Therapies

“…In type 2B VWD, recent advances have moved away from replacement therapies to investigating synthetic nanoparticles. 88 Those nanoparticles are able to concomitantly bind to VWF, collagen, and activated platelets, and therefore improve thrombus formation in vitro. Moreover, they reduced blood loss in type 2B VWD mice by 35% and in a type 3 VWD model (i.e., VWF knockout mice) by 68% with a strong clot similar to wild type mice.…”

“…Moreover, they reduced blood loss in type 2B VWD mice by 35% and in a type 3 VWD model (i.e., VWF knockout mice) by 68% with a strong clot similar to wild type mice. 88 These results and the fact that those synthetic nanoparticles have a long half-life make them a possible treatment option to be tested in future clinical trials. 88…”

“…88 These results and the fact that those synthetic nanoparticles have a long half-life make them a possible treatment option to be tested in future clinical trials. 88…”